Vaccines that are generally widely used aim to induce immunity for prevention of infectious diseases, and are used to administer pathogens (e.g., microorganisms and viruses) or a part thereof. Most of the vaccine formulations commercialized at present are injection products.
Commonly, invasive administration of a vaccine into the body is needed because microorganisms or viruses cannot enter the body through the skin due to their sizes. Injections, such as subcutaneous injection, intradermal injection, and intramuscular injection, are therefore commonly used for administration of vaccines for immunization.
Examples of adjuvants or immunostimulants practically used for immunization by injections include aluminum salts (e.g., aluminum hydroxide, aluminum phosphate, and aluminum chloride) and emulsions containing squalene (e.g., MF59 and AS03). Moreover, flagellar components, nucleic acids, cytokines, cationic polymers, polypeptides, and the like are also considered to be used as the adjuvants or immunostimulants.
Injections, however, have problems in terms of the quality of life (QOL) of the patients, such as pain, fear, needle marks and scarring thereof, and the burden of visiting the hospital in their daily life in a case where repeated administration is required. Additionally, injections further have problems that only medical practitioners can give them, that the intradermal injection which gives a high immune effect requires a proficient skill to give, that medical practitioners are exposed to a risk of infection due to needle pricking, and that medical waste which necessitate special disposition, such as injection needles, is generated. The injection is therefore not necessarily the best administration route.
The administration route of vaccines other than injections may be, for example, transdermal administration (see Patent Literature 1 and Non-Patent Literature 1), buccal administration, transnasal administration, sublingual administration (see Non-Patent Literature 2 and Patent Literatures 2 and 3), or the like.
Since a large number of Langerhans cells that are antigen presenting cells are present in the skin, transdermal administration or transmucosal administration is now considered as a means to avoid various problems in relation to injections.
Examples of the adjuvant or immunostimulants considered to be used for immunization by transdermal administration or transmucosal administration include aluminum salts (e.g., aluminum hydroxide, aluminum phosphate, and aluminum chloride) and toxins (e.g., cholera toxin and Escherichia coli heat-labile toxin).
The adjuvants or immunostimulants conventionally used for transdermal administration or transmucosal administration are limited, such as fragments derived from microorganisms or viruses, toxins (e.g., cholera toxin, Escherichia coli heat-labile toxin), and oil/fat adjuvants that enhance the effect by the extended-release of antigens. These adjuvants have a problem of a balance between the safety and the effect.
Moreover, immunostimulants effectively used in induction of humoral immunity by transdermal administration of antigens have been hardly reported. In many cases, transdermal administration fails to give a sufficient humoral immunity inducing effect in comparison with the case of using injections.
Bisphosphonates used for treatment of osteoporosis have recently been found to stimulate dendritic cells or γδT cells to activate the immune response. Bisphosphates are now expected to have a new application as immunostimulants.
However, a sufficient therapeutic effect cannot be expected from simple administration of a bisphosphonate because the proportion of γδT cells in the peripheral blood is only 1% to 5%. As a means to achieve a sufficient effect, Patent Literatures 4, 5, and 6 each teaches immuno-cell therapy in which γδT cells isolated from the patient's peripheral blood is stimulated in vitro, co-cultured with other immunocompetent cell(s), and returned to the patient's blood.
Patent Literature 7, for example, reports a case where sufficient antibody production is induced by injecting a bisphosphonate to stimulate dendritic cells or the like several days before the administration of virus antigens as a vaccine.